Transforming growth factor (TGF)-β strongly promotes generation of the extracellular matrices of mesenchymal cells, and at the same time, it suppresses the growth of epithelial cells, so as to promote pathogenesis of sclerotic diseases such as hepatic fibrosis/cirrhosis, atherosclerosis, lung fibrosis, scleroderma, or renal failure. On the other hand, TGF-β suppresses the action of immune cells. TGF-β is a multifunctional cytokine acting as a homodimer with a molecular weight of 25 kD, which exhibits various biological activities. As a result of studies using a combination of the neutralizing antibody to TGF-β and animal models, it has been revealed that sclerotic diseases can be prevented or cured by suppressing the action of TGF-β. For example, Okuno et al. Gastroenterology 120: 1784-1800, 2001 describes the prevention or treatment of hepatic fibrosis/cirrhosis by suppressing a TGF-β activation reaction using a protease inhibitor. Moreover, Akita et al. Gastroenterology 123: 352-364, 2002 describes promotion of liver regeneration by suppressing a TGF-β activation reaction using an antibody to protease. In addition, there are several review articles on TGF-β activation reaction, such as Kondo et al., Journal of the Japanese Society on Thrombosis and Hemostasis, 14 (3): 210-219, 2003, and Annes et al. J Cell Sci 116: 217-224, 2003.
On the other hand, TGF-β also plays an important role to maintain our health. For example, TGF-β suppresses excessive generation of proteases in lung and prevents lung tissue from destruction leading to emphysema. It also suppresses the growth of cancer cells, Furthermore, TGF-β has three isoforms, β1, β2 and β3, which exhibit almost the same biological activities. Thus, it has been desired to develop the technique, useful for treatment of diseases and prediction of prognosis, which detect and suppress pathogenesis-, tissues- or isoforms-specific TGF-β generation reactions, so as to block aberrant generation of a certain TGF-β isoform during the progression of pathogenesis. However, it has been difficult to detect such specific TGF-β generation reactions using the hitherto reported techniques.
Although there are established techniques to determine the isoform types of generated TGF-β in a certain lesion during pathogenesis process in animal models or patients utilizing antibodies (manufactured by R & D, or Sant Cruz) or gene probes (Bissell et al. J Clin Invest 96: 447-455, 1995) specific to each TGF-β isoform, since pathogenesis-, tissue-, or isoform-specific TGF-β generation reaction can not be detected by these techniques, these techniques have not allowed to develop a specific method for therapy or prevention of the diseases.